Macromolecular cages have three dimensional chambers surrounded by a molecular framework. Macromolecular cage architectures come in various sizes ranging from 1-50 nm and have varying topologies as well as functions. They can be synthesized through covalent bonding or self-assembly through non-covalent interactions. Most macromolecular cages that are formed through self-assembly are sensitive to pH, temperature, and solvent polarity.

Metal Organic Polyhedra

Metal Organic Polyhedra (MOPs) comprise a specific type of self-assembled macromolecular cage that is formed through unique coordination and is typically chemically and thermally stable. MOPs have cage-like frameworks with an enclosed cavity. The discrete self-assembly of metal ions and organic scaffolds to form MOPs into highly symmetrical architectures, is a modular process and has various applications. The self-assembly of various subunits that result in high symmetry is a common occurrence in biological systems. Specific examples of this are

ferritin Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. It is the primary ' ...

, capsid, and the tobacco mosaic virus, which are formed by the self-assembly of protein subunits into a polyhedral symmetry. Nonbiological polyhedra formed with metal ions and organic linkers are metal based macromolecular cages that have nanocavities with multiple openings or pores that allow small molecules to permeate and pass through. MOPs have been used to encapsulate a number of guests through various host-guest interactions (e.g. electrostatic interactions, hydrogen bonding, and steric interactions). MOPs are biomimetic materials that have potential for biomedical and biochemical applications. In order for the cage to work effectively and have biomedical relevance, it has to be chemically stable, biocompatible, and needs to operate mechanistically in aqueous media. Macromolecular cages in general can be used for a variety of applications (e.g. nanoencapsulation, biosensing, drug delivery, regulation of nanoparticle synthesis, and

catalysis Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

Cage Shaped Polymers

There are also a class of macromolecular cages that are synthetically formed through covalent bonding as opposed to self-assembly. Through the covalent-bond-forming strategy the cage molecules can be synthesized methodically with customizable functionality and regulated cavity size. Cage-shaped polymers are macromolecular analogues of molecular cages such as cryptand. A cage molecule of this type can be tuned by the

degree of polymerization The degree of polymerization, or DP, is the number of monomeric units in a macromolecule or polymer or oligomer molecule. For a homopolymer, there is only one type of monomeric unit and the ''number-average'' degree of polymerization is given by ...

. The polymers that are typically used to make the polymer based macromolecular cages are made with star shaped polymers or nonlinear polymer precursors. The molecular size of the polymeric macromolecular cage is controlled by the molecular weight of the star-shaped polymer or

branched polymer In polymer chemistry, branching is the regular or irregular attachment of side chains to a polymer's backbone chain. It occurs by the replacement of a substituent (e.g. a hydrogen atom) on a monomer subunit by another covalently-bonded ch ...

. The macromolecular cages made from non-linear polymers are designed to have molecular recognition, respond to external stimuli and self-assemble into higher order structures.

Fullerenes

Fullerenes are a class of carbon allotropes that were first discovered in 1985 and are also an example of macromolecular cages. Buckminsterfullerene (C₆₀) and the 60 atoms of this molecule are arranged in a cage-like structure and the framework resembles a soccer ball; the molecule has an icosahedral symmetry. C₆₀ has versatile applications due to its macromolecular cage structure; for example, it can be used for water purification, catalysis, bio-pharmaceuticals, serve as a carrier of

radionuclide A radionuclide (radioactive nuclide, radioisotope or radioactive isotope) is a nuclide that has excess nuclear energy, making it unstable. This excess energy can be used in one of three ways: emitted from the nucleus as gamma radiation; transfer ...

s for MRI, and drug delivery.

Macromolecular Cage Architecture in Biology

There are many examples of highly symmetrical macromolecular cage motifs known as protein cages in biological systems. The term ''protein cage'' delineates a diverse range of protein structures that are formed by the self-assembly of protein subunits into hollow macromolecular nanoparticles. These protein cages are nanoparticles that have one or more cavities present in their structure. The size of the cavity contributes to the size of the particle that the cavity can enclose, for example inorganic nanoparticles, nucleic acids, and even other proteins. The interior or chamber portion of the protein cage is usually accessible through a pore which is located in between protein subunits. The RNA

exosome Exosome may refer to: * Exosome complex The exosome complex (or PM/Scl complex, often just called the exosome) is a multi-protein intracellular complex capable of degrading various types of RNA (ribonucleic acid) molecules. Exosome complexes ...

has

nuclease A nuclease (also archaically known as nucleodepolymerase or polynucleotidase) is an enzyme capable of cleaving the phosphodiester bonds between nucleotides of nucleic acids. Nucleases variously effect single and double stranded breaks in their ta ...

active sites that are present in a cavity where 3' RNA degradation takes place; access to this cavity is controlled by a pore and this serves to prevent uncontrollable RNA decay. Some protein cages are dynamic structures that assemble and disassemble in response to external stimuli. Other examples of protein cages are clathrin cages, viral envelopes,

chaperonin HSP60, also known as chaperonins (Cpn), is a family of heat shock proteins originally sorted by their 60kDa molecular mass. They prevent misfolding of proteins during stressful situations such as high heat, by assisting protein folding. HSP60 bel ...

s, and the iron storage protein

Synthetic Strategies to form Macromolecular Cages

There are various methods used to form polymeric macromolecular cages. One synthetic method uses ring opening and multiple

click chemistry In chemical synthesis, click chemistry is a class of biocompatible small molecule reactions commonly used in bioconjugation, allowing the joining of substrates of choice with specific biomolecules. Click chemistry is not a single specific reaction ...

in the first step to form trefoil and quatrefoil-shaped polymers, which can then be topologically converted into cages using

hydrogenolysis Hydrogenolysis is a chemical reaction whereby a carbon–carbon or carbon–heteroatom single bond is cleaved or undergoes lysis (breakdown) by hydrogen.Ralph Connor, Homer Adkins. Hydrogenolysis Of Oxygenated Organic Compounds. J. Am. Chem. Soc. ...

. The initiator in this synthesis is azido and hydroxy functionalized ''p''-xylene and the monomer is

butylene oxide Epoxybutane may refer to: * 1,2-Epoxybutane * 1,4-Epoxybutane (tetrahydrofuran) * 2,3-Epoxybutane {{Short pages monitor Epoxides ...

. The ring opening polymerization and simultaneous click cyclizations of butylene oxide with the initiator is catalyzed by ''t''-Bu-P₄. This synthetic strategy was used to form cage-shaped polybutylene oxides; cage-shaped block copolymers are also formed using a similar method. One synthetic strategy utilizes

atom transfer radical polymerization Atom transfer radical polymerization (ATRP) is an example of a reversible-deactivation radical polymerization. Like its counterpart, ATRA, or atom transfer radical addition, ATRP is a means of forming a carbon-carbon bond with a transition metal cat ...

and click chemistry methods to form figure eight and cage-shaped

polystyrene Polystyrene (PS) is a synthetic polymer made from monomers of the aromatic hydrocarbon styrene. Polystyrene can be solid or foamed. General-purpose polystyrene is clear, hard, and brittle. It is an inexpensive resin per unit weight. It is a ...

; in this case the precursor is nonlinear polystyrene. Another synthetic strategy employs intramolecular ring-opening metathesis oligomerization of a star polymer and this reaction method is catalyzed by diluted Grubb's third generation catalyst.

Covalent Organic Frameworks Covalent organic frameworks (COFs) are a class of materials that form two- or three-dimensional structures through reactions between organic precursors resulting in strong, covalent bonds to afford porous, stable, and crystalline materials. COFs em ...

(COFs) have also been used to form cage architectures and in one such example Schiff base cyclization was used to form the macromolecular cage molecule. In this synthesis 1,3,5-triformylbenzene and (''R,R'')-(1,2)-diphenylethylenediamine undergo cycloimination in dichloromethane with

trifluoroacetic acid Trifluoroacetic acid (TFA) is an organofluorine compound with the chemical formula CF3CO2H. It is a structural analogue of acetic acid with all three of the acetyl group's hydrogen atoms replaced by fluorine atoms and is a colorless liquid with a ...

as a catalyst to form a COF cage molecule.

Macrocyclization Macrocycles are often described as molecules and ions containing a ring of twelve or more atoms. Classical examples include the crown ethers, calixarenes, porphyrins, and cyclodextrins. Macrocycles describe a large, mature area of chemistry. ...

s have also been employed to form

peptoid Peptoids (root from the Greek language, Greek πεπτός, ''peptós'' "digested"; derived from πέσσειν, ''péssein'' "to digest" and the Greek-derived suffix -oid meaning "like, like that of, thing like a ______," ), or poly-''N''-substit ...

based macromolecular cages, the specific methodology utilizes a one pot synthesis to form steroid-aryl hybrid cages using two- and three-fold Ugi type macrocyclization reactions.

Genetically engineered macromolecular cages made from biomolecules

Macromolecular cages can also be formed synthetically using biomolecules. Protein cages can be genetically engineered, and the outside of the cage can be tailored with synthetic polymers, which is known as protein-polymer conjugation. Preformed polymer chains can be attached to the surface of the protein using chemical linkers. Polymerization can also occur from the protein surface, and the polymer can also be bound to the surface of protein cages via electrostatic interactions. The purpose of this modification is to make synthetic protein cages more biocompatible; this post synthetic modification makes the protein cage less susceptible to an immune response and stabilizes the cage from degradation from

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...

s. Virus-like protein (VLP) cages have also been synthesized and

recombinant DNA technology Molecular cloning is a set of experimental methods in molecular biology that are used to assemble recombinant DNA molecules and to direct their replication within host organisms. The use of the word ''cloning'' refers to the fact that the metho ...

is used to form non-native virus-like proteins. The first reported case of the formation of non-native VLP constructs into a capsid-like structure utilized a functionalized gold core for nucleation. The self-assembly of the VLP was initiated by the electrostatic interaction of the functionalized gold nanoparticles which is similar to the interaction of a native virus with its nucleic acid component. These viral protein cages have potential applications in biosensing and medical imaging.

DNA origami DNA origami is the nanoscale folding of DNA to create arbitrary two- and three-dimensional shapes at the nanoscale. The specificity of the interactions between complementary base pairs make DNA a useful construction material, through design of ...

is another strategy to form macromolecular cages or containers. In one case, a 3D macromolecular cage with icosahedral symmetry (resembling viral capsids) was formed based on the synthetic strategy in 2D origami. The structure had an inside volume or hollow cavity encased by triangular faces, similar to a pyramid. This close-faced cage was designed to potentially encapsulate other materials such as proteins and metal nanoparticles.

References

{{Reflist Macromolecules